Tomas Navratil

Czech mass methanol outbreak 2012: Epidemiology, challenges and clinical features

Abstract Objectives. Methanol poisonings occur frequently globally, but reports of larger outbreaks where complete clinical and laboratory data are reported remain scarce. The objective of the present study was to report the data from the mass methanol poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was provided to the most severely poisoned patients in the critical phase. Methods. A combined prospective and retrospective case series study of 121 patients with confirmed methanol poisoning. Results. From a total of 121 intoxicated subjects, 20 died outside the hospital and 101 were hospitalized. Among them, 60 survived without, and 20 with visual/CNS sequelae, whereas 21 patients died. The total and hospital mortality rates were 34% and 21%, respectively. Multivariate regression analysis found pH < 7.0 (OR 0.04 (0.01–0.16), p < 0.001), negative serum ethanol (OR 0.08 (0.02–0.37), p < 0.001), and coma on admission (OR 29.4 (10.2–84.6), p < 0.001) to be the only independent parameters predicting death. Continuous hemodialysis was used more often than intermittent hemodialysis, but there was no significant difference in mortality rate between the two [29% (n = 45) vs 17% (n = 30), p = 0.23]. Due to limited stockpiles of fomepizole, ethanol was administered more often; no difference in mortality rate was found between the two [16% (n = 70) vs. 24% (n = 21), p = 0.39]. The effect of folate administration both on the mortality rate and on the probability of visual sequelae was not significant (both p > 0.05). Conclusions. Severity of metabolic acidosis, state of consciousness, and serum ethanol on admission were the only significant parameters associated with mortality. The type of dialysis or antidote did not appear to affect mortality. Recommendations that were issued for hospital triage of fomepizole administration allowed conservation of valuable antidote in this massive poisoning outbreak for those patients most in need.

Markers of oxidative damage of nucleic acids and proteins among workers exposed to TiO2 (nano) particles

Objective The use of nanotechnology is growing enormously and occupational physicians have an increasing interest in evaluating potential hazards and finding biomarkers of effect in workers exposed to nanoparticles. Methods A study was carried out with 36 workers exposed to (nano)TiO2 pigment and 45 controls. Condensate (EBC) titanium and markers of oxidation of nucleic acids (including 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5-hydroxymethyl uracil (5-OHMeU)) and proteins (such as o-tyrosine (o-Tyr), 3-chlorotyrosine (3-ClTyr) and 3-nitrotyrosine (3-NOTyr)) were analysed from samples of their exhaled breath. Results In the production workshops, the median total mass 2012 and 2013 TiO2 concentrations were 0.65 and 0.40u2005mg/m3, respectively. The median numbers of concentrations measured by the scanning mobility particle sizer (SMPS) and aerodynamic particle sizer (APS) were 1.98×104 and 2.32×104 particles/cm3, respectively; and about 80% of those particles were smaller than 100u2005nm in diameter. In the research workspace, lower aerosol concentrations (0.16u2005mg/m3 and 1.32×104 particles/cm3) were found. Titanium in the EBC was significantly higher in production workers (p<0.001) than in research workers and unexposed controls. Accordingly, most EBC oxidative stress markers, including in the preshift samples, were higher in production workers than in the two other groups. Multiple regression analysis confirmed an association between the production of TiO2 and the levels of studied biomarkers. Conclusions The concentration of titanium in EBC may serve as a direct exposure marker in workers producing TiO2 pigment; the markers of oxidative stress reflect the local biological effect of (nano)TiO2 in the respiratory tract of the exposed workers.

Is the Measurement of Serum Formate Concentration Useful in the Diagnostics of Acute Methanol Poisoning? A Prospective Study of 38 Patients

The aim of this article was to study the role of serum formate (S‐formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 – median age 51 [interquartile range (IQR) 37–62] years with confirmed methanol poisoning. S‐formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S‐formate. Asymptomatic patients had median S‐formate of 1.9 (IQR 1.5–2.4) mmol/L. The median S‐formate was 15.2 (IQR 13.9–17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1–18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8–18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long‐term visual sequelae of poisoning had median S‐formate of 16.1 (IQR 14.3–19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2–19.5) mmol/L. In lethal cases, the median S‐formate was 15.2 (IQR 13.8–15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S‐formate ≥17.5 mmol/L, S‐lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44–0.85 CI 95%) for S‐formate, 0.75 (0.56–0.93 CI 95%) for ‘S‐formate+S‐lactate’ and only 0.54 (0.38–0.69 CI 95%) for serum methanol, which is lower than for S‐formate (p < 0.05). The measurement of S‐formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S‐formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S‐formate ≥11–12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.

Long-term visual damage after acute methanol poisonings: Longitudinal cross-sectional study in 50 patients

Context. Visual disturbances due to the toxic effect of formic acid in acute methanol poisonings are generally transient. The subjective symptoms of visual toxicity may resolve within few weeks and fundoscopic signs of acute optic neuropathy subside within 1–2 months; therefore, the prevalence of long-term visual sequelae in the population of survivors of poisonings may be underestimated. Objective. To study the prevalence and character of long-term visual sequelae of acute methanol poisonings based on the data from the Czech mass methanol outbreak in 2012. Patients and methods. A total of 50 patients with confirmed methanol poisoning were included in this longitudinal cross-sectional study, median age: 48 (range, 23–73) years. The following tests were performed: optical coherence tomography or OCT with evaluation of the retinal nerve fibers layer (RNFL), visual evoked potentials (VEP), magnetic resonance imaging (MRI) of brain, complete ocular examination (visual acuity/field, color vision, contrast sensitivity, and fundus), neurological examinations, and biochemical tests. Results. Of 50 patients, 7/50 (14%) were discharged with diagnosed visual sequelae and 6/50 (12%) were discharged with both visual and central nervous system sequelae of poisoning. On the follow-up examination, 20/50 (40%) of the patients had long-term visual sequelae, with 8% of blindness. A total of 38% of the patients had abnormal (28% borderline) findings on RNFL, and 40% had abnormal (18% borderline) VEP. Among the patients discharged without detected visual sequelae, 8/37 (22%) had abnormal RNFL and VEP. Patients with visual sequelae had brain lesions more often (70% vs. 27%, p < 0.01). MRI identified optic nerve lesions in 2/20 cases with abnormal VEP only. The groups with and without visual sequelae differed in serum methanol, ethanol, HCO3-, formate, pH, anion gap, and base deficit (all p < 0.01). Visual disturbances on admission and coma were more prevalent in the patients with visual sequelae (p < 0.05). Patients with positive serum ethanol on admission were 93% less likely to have optical axonal damage (OR: 0.07 (95% CI: 0.01–0.8); p < 0.05). No association was found between visual sequelae and type of antidote administered, mode of hemodialysis, or folate substitution. Pre-hospital administration of ethanol seemed beneficial: these patients were 90% less likely to have abnormal RNFL findings (OR: 0.10 (95% CI: 0.02–0.52); p < 0.01). Conclusions. The long-term visual sequelae were clearly underestimated on discharge, suggesting a significantly higher amount of patients with long-term sequelae than earlier reported. Thorough examinations before discharge and during follow-up will likely uncover a higher morbidity also after methanol poisonings in general.

Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak

Abstract Context. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case–control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. Results. Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p < 0.001) and late-presenting (>12 h; p = 0.028) patients received fomepizole more often than ethanol, as reflected in the higher number of fomepizole-treated patients being intubated (p = 0.009). No association was found between the type of antidote and the survival in either the case series (p = 0.205) or the quasi-control groups (p = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9–39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3–10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2–22) days in the fomepizole group and 4 (range, 1–33) days in the ethanol group (p = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n = 100), nor the case–control groups (n = 50)). Conclusions. This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness.

Raman microspectroscopy of exhaled breath condensate and urine in workers exposed to fine and nano TiO2 particles: a cross-sectional study.

The health effects of engineered nanoparticles in humans are not well-understood; however experimental data support the theory of oxidative stress promoting fibrogenesis and carcinogenicity. The aim of this study was to detect TiO2 particles in exhaled breath condensate (EBC) and urine samples to ascertain their presence and potential persistence and excretion in urine.EBC and urine samples were collected from 20 workers exposed to TiO2 aerosol; among them, 16 had a higher risk level of exposure (production workers) and four had medium risk level (research workers); in addition to 20 controls. Titanium levels in EBC and urine were analysed using the inductively coupled plasma mass spectrometry (ICP-MS) method. A Raman microspectroscopic analysis was performed in EBC and urine to identify the phase composition of TiO2 particles observed. Aerosol exposure in the workplaces was measured using SMPS and APS spectrometers and P-TRAK and DustTRAK DRX monitors.The median concentration of TiO2 aerosol was 1.98xa0×xa010(4) particlesu2009cm(-3), the interquartile range (IQR) was 1.50xa0×xa010(4)xa0-xa03.01xa0×xa010(4) particlesu2009cm(-3) and the median mass concentration was 0.65u2009mgu2009m(-3) (IQR 0.46-.0.83u2009mgu2009m(-3)); 70-82% of the particles were smaller than 100u2009nm in diameter. In any part of the plant, the median TiO2 air concentration did not exceed the national airborne exposure limit of 10u2009mgu2009m(-3) for inert dust. Particles of rutile and/or anatase were found in the EBC of exposed workers in 8/20 (40%) of the pre-shift and 14/20 (70%) of the post-shift samples. In the urine of workers, TiO2 particles were detected in 2/20 post-shift urine samples only. The mean concentration of titanium in the EBC in production workers was 24.1xa0±xa01.8u2009µg/l. In the research workers the values were below the limit of quantitation; LOQ = 4.0xa0±xa00.2u2009µg/l), as well as in the controls. In the urine samples of all of the subjects, titanium was under the limit of detection (LOD = 1.2u2009µg/l). Raman microanalysis of EBC in the workers confirmed the presence of TiO2 anatase and/or rutile crystal phases in the pre-shift samples and their persistence from previous shifts in the workers.

Use of Out-of-Hospital Ethanol Administration to Improve Outcome in Mass Methanol Outbreaks

STUDY OBJECTIVEnMethanol poisoning outbreaks are a global public health issue, with delayed treatment causing poor outcomes. Out-of-hospital ethanol administration may improve outcome, but the difficulty of conducting research in outbreaks has meant that its effects have never been assessed. We study the effect of out-of-hospital ethanol in patients treated during a methanol outbreak in the Czech Republic between 2012 andxa02014.nnnMETHODSnThis was an observational case-series study of 100 hospitalized patients with confirmed methanol poisoning. Out-of-hospital ethanol as a first aid antidote was administered by paramedic or medical staff before the confirmation of diagnosis to 30 patients; 70 patients did not receive out-of-hospital ethanol from the staff (12 patients self-administered ethanol shortly before presentation).nnnRESULTSnThe state of consciousness at first contact with paramedic or medical staff, delay to admission, and serum methanol concentration were similar among groups. The median serum ethanol level on admission in the patients with out-of-hospital administration by paramedic or medical staff was 84.3 mg/dL (interquartile range 32.7 to 129.5 mg/dL). No patients with positive serum ethanol level on admission died compared with 21 with negative serum ethanol level (0% versus 36.2%). Patients receiving out-of-hospital ethanol survived without visual and central nervous system sequelae more often than those not receiving it (90.5% versus 19.0%). A positive association was present between out-of-hospital ethanol administration by paramedic or medical staff, serum ethanol concentration on admission, and both total survival and survival without sequelae of poisoning.nnnCONCLUSIONnWe found a positive association between out-of-hospital ethanol administration and improved clinical outcome. During mass methanol outbreaks, conscious adults with suspected poisoning should be considered for administration of out-of-hospital ethanol to reduce morbidity and mortality.

Fomepizole in the treatment of acute methanol poisonings: Experience from the Czech mass methanol outbreak 2012-2013

OBJECTIVEnDuring an outbreak of mass methanol poisonings in the Czech Republic in 2012-2013, fomepizole was applied as an alternative antidote to ethanol. We present the laboratory data, clinical features, adverse reactions, and treatment outcomes in all patients treated with fomepizole.nnnMETHODSnCombined retrospective and prospective case series study in 25 patients, median age 50 (16-73) years, 18 males and 7 females.nnnRESULTSnThere were 24% fatalities, 36% survivors without health impairment, and 40% survivors with sequelae. All the patients who died were comatose on admission; the mortality was 50% among patients in a coma. The median intensive care unit length of stay was six (2-22) days. The median total dose of fomepizole was 2 (1-9) g. Complications were observed in 7/25 cases: aspiration pneumonia (4), sepsis (2), bleeding (2), malignant arrhythmia (1), delirium tremens (1), and rebound of acidosis (1). The patients who survived without impairment were less acidotic than those who died or survived with sequelae (P<0.01). No difference in serum methanol and formate was found between the three groups.nnnCONCLUSIONnThere is no evidence whether fomepizole is a more efficient antidote than ethanol with regards to the hospital mortality. The possibility of delirium tremens in the patients with a history of chronic alcohol abuse has to be taken in consideration. The benefits of fomepizole were indirect: no need to monitor serum ethanols level during the hemodialysis in severely poisoned patients and less working overload on ICU doctors treating several poisoned patients simultaneously.

Fluctuations in serum ethanol concentration in the treatment of acute methanol poisoning: a prospective study of 21 patients

OBJECTIVEnDuring the 2012 outbreak of mass methanol poisonings in the Czech Republic, ethanol, in the main, was used as an antidote. The complex pharmacokinetics of ethanol made it difficult to maintain the requisite 1000-1500 mg/L serum ethanol levels (S-EtOH). The aim of this study was to measure the fluctuations in S-EtOH during the treatment.nnnMETHODSnA prospective case series in 21 patients, median age 52 (27-79 years), 13 males and 8 females. Serum ethanol, methanol and formate were measured every 2-6 hours during the treatment. Follow-up clinical examination was carried out in 15/18 survivors.nnnRESULTSnThe majority of patients (17/21) were late presenters and on admission, almost half (10/21) had suffered a severe grade of intoxication according to the Poisoning Severity Score (PSS). The mean observation time was 90±20 h. The mean period of consistent maintenance of S-EtOH within the recommended therapeutic range lasted 28±7% of the total observation time. For 29±8% of the time, S-EtOH was >1500 mg/L with peaks of up to 3500 mg/L. For 44±10% of the observation time, S-EtOH was <1000 mg/L. The mean duration of sub-therapeutic concentration of S-EtOH and toxic serum levels of methanol >200 mg/L or formate >20 mg/L lasted 20±10% and 18±11% of the time of observation, respectively. Complications occurred in 14 (67%) of cases including significant fluctuations of S-EtOH in 9; aspiration pneumonia in 3 and delirium tremens in 2 cases. Other complications included sepsis, bleeding, acidosis rebound, intolerance and set clotting. The outcomes were: 11 survivors free of health impairment, 7 with sequelae and 3 deaths. There was no significant difference in mean duration of sub-therapeutic and supra-therapeutic concentrations of serum ethanol in patients who survived without sequelae and those with poor outcome (P > 0.05).nnnCONCLUSIONnAdministration of ethanol according to the present guidelines of the AACT/EAPCCT is effective and relatively safe in the treatment of methanol poisoning during a mass outbreak(31). Physicians have to be most aware of fluctuations in serum ethanol at the end of short sessions of IHD and after changes in route from intravenous to oral. Rigorous monitoring of serum ethanol concentrations is pivotal for severely poisoned patients with PSS 3 and where there is suspected conversion of significant amounts of methanol to formic acid.

Efficiency of acidemia correction on intermittent versus continuous hemodialysis in acute methanol poisoning.

Abstract Context: Acidemia is a marker of prognosis in methanol poisoning, as well as compounding formate-induced cytotoxicity. Prompt correction of acidemia is a key treatment of methanol toxicity and methods to optimize this are poorly defined. Objective: We studied the efficiency of acidemia correction by intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) in a mass outbreak of methanol poisoning. Methods: The study was designed as observational cohort study. The mean time for an increase of 1u2009mmol/L HCO3–, 0.01 unit arterial blood pH, and the total time for correction of HCO3– were determined in IHD- and CRRT-treated patients. Results: Data were obtained from 18 patients treated with IHD and 13 patients treated with CRRT. At baseline, CRRT group was more acidemic than IHD group (mean arterial pH 6.79u2009±u20090.10 versus 7.05u2009±u20090.10; pu2009=u20090.001). No association was found between the rate of acidemia correction and age, weight, serum methanol, lactate, formate, and glucose on admission. The time to HCO3– correction correlated with arterial blood pH (r=u2009−0.511; pu2009=u20090.003) and creatinine (ru2009=u20090.415; pu2009=u20090.020). There was association between the time to HCO3– correction and dialysate/effluent and blood flow rates (r=u2009−0.738; pu2009<u20090.001 and r=u2009−0.602; pu2009<u20090.001, correspondingly). The mean time for HCO3– to increase by 1u2009mmol/L was 12u2009±u20092u2009min for IHD versus 34u2009±u20098u2009min for CRRT (pu2009<u20090.001), and the mean time for arterial blood pH to increase 0.01 was 7u2009±u20091 mins for IHD versus 11u2009±u20094u2009min for CRRT (pu2009=u20090.024). The mean increase in HCO3– was 5.67u2009±u20090.90u2009mmol/L/h for IHD versus 2.17u2009±u20090.74u2009mmol/L/h for CRRT (pu2009<u20090.001). Conclusions: Our study supports the superiority of IHD over CRRT in terms of the rate of acidemia correction.